US4977138A - FR901228 substance and preparation thereof - Google Patents

FR901228 substance and preparation thereof Download PDF

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Publication number
US4977138A
US4977138A US07/375,998 US37599889A US4977138A US 4977138 A US4977138 A US 4977138A US 37599889 A US37599889 A US 37599889A US 4977138 A US4977138 A US 4977138A
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US07/375,998
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Inventor
Masakuni Okuhara
Toshio Goto
Yasuhiro Hori
Takashi Fujita
Hirotsugu Ueda
Nobuharu Shigematsu
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Astellas Pharma Inc
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Fujisawa Pharmaceutical Co Ltd
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Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Assigned to FUJISAWA PHARMACEUTICAL CO., LTD. reassignment FUJISAWA PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: FUJITA, TAKASHI, GOTO, TOSHIO, HORI, YASUHIRO, OKUHARA, MASAKUNI, SHIGEMATSU, NOBUHARU, UEDA, HIROTSUGU
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Assigned to ASTELLAS PHARMA INC. reassignment ASTELLAS PHARMA INC. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: FUJISAWA PHARMACEUTICAL CO., LTD.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to a new compound having a biological activity, hereinafter referred to as FR901228 substance. More particularly, this invention relates to a new biologically active FR901228 substance, which has antimicrobial and antitumor activities, to a process for its preparation, and to pharmaceutical compositions comprising the same.
  • FR901228 substance of this invention can be produced by fermentation of FR901228 substance-producing strain belonging to the genus Chromobacterium such as Chromobacterium violaceum WB968 in a nutrient medium.
  • Strain WB968 was isolated from a soil sample obtained from Yamagata-ken, JAPAN.
  • Strain WB968 was a gram-negative, motile bacterium.
  • the cell shapes were rod and about 0.5-0.6 ⁇ 1.2-1.8 ⁇ m in
  • Physiological characteristics of the strain WB968 were summarized in Table 2.
  • the growth temperature range was from 15° C. to 40° C.
  • strain WB968 was oxidase positive, catalase positive and O-F test fermentative. Casein was hydrolyzed and esculin hydrolysis was negative. Glucose, fructose and trehalose were fermented. Indole test was negative. Voges-Preskauer test was negative. And ⁇ -galactosidase test (ONPG test) was negative.
  • FR901228 substance of this invention is produced when a FR901228 substance-producing strain belonging to the genus Chromobacterium (e. g. Chromobacterium violaceum WB968) is grown in a nutrient medium containing sources of assimilable carbon and nitrogen under aerobic conditions (e. g. shaking culture, submerged culture, etc.).
  • Chromobacterium e. g. Chromobacterium violaceum WB968
  • sources of assimilable carbon and nitrogen e. g. shaking culture, submerged culture, etc.
  • the preferred sources of carbon in the nutrient medium are carbohydrates such as glucose, starch, fructose or glycerin.
  • the preferred sources of nitrogen are bouillon, yeast extract, peptone, gluten meal, cotton seed flour, soybean meal, corn steep liquor, dried yeast, wheat germ, etc., as well as inorganic and organic nitrogen compounds such as ammonium salts (e. g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.), urea or amino acid.
  • ammonium salts e. g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.
  • urea or amino acid e. g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.
  • the carbon and nitrogen sources though advantageously employed in combination, need not to be used in their pure form because less pure materials, which contain traces of growth factors and considerable quantities of mineral nutrients, are also suitable for use.
  • medium mineral salts such as sodium or calcium carbonate, sodium or potassium phosphate, sodium or potassium chloride, sodium or potassium iodide, magnesium salts, copper salts, or cobalt salts.
  • a defoaming agent such as liquid paraffin, fatty oil, plant oil, mineral oil or silicone may be added.
  • the vegetative cells of the bacterium when the growth is carried out in large tanks, it is preferable to use the vegetative cells of the bacterium for inoculation in the production tanks in order to avoid growth lag in the process of production of FR901228 substance. Accordingly, it is desirable first to produce a vegetative cells of the bacterium by inoculating a relatively small quantity of culture medium with cells of the bacterium and culturing said inoculated medium, and then to transfer the cultured vegetative cells to large tanks.
  • the medium, in which the vegetative cells is produced is substantially the same as or different from the medium utilized for the production of FR901228 substance.
  • Agitation and aeration of the culture mixture may be accomplished in a variety of ways. Agitation may be provided by a propeller or similar mechanical agitation equipment, by revolving or shaking the fermentor, by various pumping equipment or by the passage of sterile air through the medium. Aeration may be effected by passing sterile air through the fermentation mixture
  • the fermentation is usually conducted at a temperature between about 10° C. and 40° C., preferably 25° C. to 35° C., for a period of about 15 hours to 50 hours, which may be varied according to fermentation conditions and scales.
  • the culture broth is then subjected for the recovery of FR901228 substance to various processes conventionally used for recovery and purification of biological active substances, for instance, solvent extraction with an appropriate solvent or a mixture of some solvents, chromatography or recrystallization from an appropriate solvent or a mixture of some solvents
  • FR901228 substance is found mainly in the cells of the bacterium.
  • the filtrate also includes FR901228 substance.
  • the whole culture broth is directly subjected to the isolation process of FR901228 substance, for example, by means of extraction using an appropriate solvent such as hot water, acetone or ethyl acetate, or a mixture of these solvents
  • the extract is treated by a conventional manner to provide FR901228 substance, for example, the extract is concentrated by evaporation or distillation to a smaller amount and the resulting residue containing active material, i. e. FR901228 substance is purified by conventional purification processes, for example, chromatography or recrystallization from an appropriate solvent or a mixture of some solvents.
  • FIGS. 1--3 Physico-chemical properties of FR901228 substance are shown in FIGS. 1--3.
  • FIG. 1 illustrates its infrared absorption spectrum
  • FIG. 2 illustrates its 1 H nuclear magnetic resonance spectrum
  • FIG. 3 illustrates its 13 C nuclear magnetic resonance spectrum.
  • FR901228 substance as obtained according to the aforementioned fermentation process has the following physico-chemical properties.
  • Solubility soluble: chloroform, ethyl acetate sparingly soluble: methanol, ethanol insoluble: water, hexane.
  • Color reaction positive: cerium sulfate reaction, sulfuric acid reaction, iodine vapor reaction. negative: ninhydrin reaction, ferric chloride reaction, Ehrlich reaction, Molish reaction.
  • FR901228 substance (4 mg) was hydrolyzed at 110° C. for 20 hours with 6N hydrochloric acid (2 ml) in a sealed tube. The mixture was analyzed on an automatic amino acid analyzer. The result of the amino acid analysis on FR901228 substance revealed the presence of valine and ammonia (the ratio of valine and ammonia is 2:1).
  • FR901228 substance is proved to have the following chemical formula: ##STR2##
  • Infrared absorption spectrum ⁇ max KBr 3260, 2920, 2400, 1720, 1620, 1510, 1430, 1260, 1200, 1010 cm -1 .
  • FR125441 substance (10 mg) in pyridine (0.8 ml) was added acetic anhydride (0.4 ml). After stirring for 12 hours at room temperature, solvent was evaporated. The residue was subjected to preparative thin layer chromatography (0.5 mm ⁇ 1) and developed with 5% methanol in chloroform to give FR123393 substance (10 mg).
  • FR901228 substance 54 mg
  • dioxane 2 ml
  • triphenylphosphine 55 mg
  • the solvent was removed in vacuo.
  • the residue was subjected to preparative thin layer chromatography (0.5 mm ⁇ 2) and developed with 2% methanol in chloroform to give FR123395 substance (10 mg).
  • Antimicrobial activity of FR901228 was performed by an agar dilution method in Sabouraud medium.
  • MIC Minimum inhibitory concentration
  • the cytotoxicity test was performed in microtiter plates, with each well containing 3 ⁇ 103 tumor cells in 100 ⁇ l Dulbecco's minimum essential medium supplemented with 10% fetal calf serum, penicillin (50 units/ml) and streptomycin (50 ⁇ g/ml). The cells were incubated at 37° C. for four days and the colorimetric MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, made by Sigma] assay was performed according to the method described by Mosmann (J. Immunol. Methods, 65, 55-63, 1983).
  • MTT was dissolved in phosphate buffer solution (PBS) at 5 mg/ml and filtered to sterilize and remove a small amount of insoluble residue. After the culture of human tumor cells was terminated, this MTT solution (10 ⁇ l per 100 ⁇ l medium) was added to all wells of an assay, and plates were further incubated at 37° C. for 4 hours. Acid-isopropanol (100 ⁇ l of 0.04N HCl in isopropanol) was added to all wells and mixed thoroughly to dissolve the dark blue crystals.
  • PBS phosphate buffer solution
  • FR901228 substance Antitumor activity of FR901228 substance was determined in murine tumor system. P388 leukemia cells (1 ⁇ 106) were implanted intraperitoneally into BDFl mice (female, 8 weeks old). Twenty-four hours after the inoculation of tumor cells, FR901228 substance was administered intraperitoneally to mice. Administrations of FR901228 substance were continued intraperitoneally once daily for another three days. FR901228 substance was suspended in 0.9% saline. Control mice received intraperitoneal doses of 0.9% saline.
  • Antitumor activity was expressed as the mean survival time of group and also expressed as the T/C % (100 ⁇ treated group/control group) of mean survival time.
  • the pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains FR901228 substance, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, oral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. And, if necessary, in addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • FR901228 substance may be included in the pharmaceutical composition in an amount sufficient to produce the desired antitumor effect upon the process or condition of diseases.
  • FR901228 substance For applying the composition to human, it is preferable to apply it by intravenous, intramuscular or oral administration. While the dosage of therapeutically effective amount of FR901228 substance varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.1-100 mg of FR901228 substance per kg weight of human being, in the case of intramuscular administration, a daily dose of 0.1-100 mg of FR901228 substance per kg weight of human being, in case of oral administration, a daily dose of 0.1-100 mg of FR901228 substance per kg weight of human being is generally given for treating tumor.
  • a culture medium (160 ml) containing glucose (1%) and bouillon (1%) was poured into each of 500 ml Erlenmeyer flasks and sterilized at 120° C. for 30 minutes.
  • a loopful of slant culture of Chromobacterium violaceum WB968 was inoculated to each of the medium and cultured at 30° C. for 24 hours on a rotary shaker.
  • the resultant culture was inoculated to a medium containing glucose (1%), bouillon (1%) and Adekanol (deforming agent, trade mark, made by Asahi Denka Kogyo Co.) (0.05%) (15 liters) in each of twelve 30-liter jar-fermentors, which has been sterilized at 120° C. for 30 minutes in advance, and cultured at 30° C. for 24 hours under aeration of 20 liters/minute and agitation of 200 rpm.
  • each jar-fermentor was sterilized at 120° C. for 30 minutes.
  • the culture broth thus obtained was filtered with an aid of diatomaseous earth (10 kg).
  • the filtrate (150 liters) was extracted twice with ethyl acetate (150 liters).
  • the extract was evaporated under reduced pressure to give an oily residue.
  • the oily residue was mixed with 500 g of silica gel (Kiesel gel 60, 70-230 mesh, made by E. Merck), and this mixture was slurried in methanol. After evaporating the solvent, the resultant dry powder was subjected to column chromatography of the same silica gel (0.5 liter) which was packed with n-hexane.
  • FR901228 substance in the form of slightly yellowish powder. This powder was dissolved in a mixture of dichloromethane and methanol (10:1 v/v, 10 ml). To this solution was added acetonitrile (20 ml). This was kept at room temperature and purified FR901228 substance (920 mg) was obtained as colorless crystals.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Reinforced Plastic Materials (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
US07/375,998 1988-07-26 1989-07-06 FR901228 substance and preparation thereof Expired - Lifetime US4977138A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8817743 1988-07-26
GB888817743A GB8817743D0 (en) 1988-07-26 1988-07-26 Fr901228 substance & preparation thereof

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US (1) US4977138A (fr)
EP (1) EP0352646B1 (fr)
JP (1) JPH0764872B2 (fr)
CN (1) CN1040054A (fr)
AT (1) ATE94561T1 (fr)
AU (1) AU3829089A (fr)
CA (1) CA1335083C (fr)
DE (1) DE68909139T2 (fr)
DK (1) DK366889A (fr)
ES (1) ES2058411T3 (fr)
FI (1) FI893359A (fr)
GB (1) GB8817743D0 (fr)
HU (1) HU211514A9 (fr)
IL (1) IL90949A0 (fr)
NO (1) NO893021L (fr)
ZA (1) ZA895121B (fr)

Cited By (43)

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US5130414A (en) * 1989-11-30 1992-07-14 Arizona Board Of Regents, A Body Corporate Of Arizona State University Isolation and structural elucidation of the cyclic peptide hymenistatin 1
US5428175A (en) * 1993-02-22 1995-06-27 Snow Brand Milk Products Co., Ltd. Physiologically active compound
US6403555B1 (en) 1999-12-08 2002-06-11 Xcyte Therapies, Inc. Depsipeptide and congeners thereof for use as immunosuppressants
US20030186388A1 (en) * 2000-09-01 2003-10-02 Satoshi Ueda Method of producing fr901228
US20040053820A1 (en) * 2000-07-17 2004-03-18 Hidenori Nakajima Reduced fk228 and use thereof
US20040132643A1 (en) * 2002-01-09 2004-07-08 Fojo Antonio Tito Histone deacelylase inhibitors in diagnosis and treatment of thyroid neoplasms
US6828302B1 (en) 1999-12-08 2004-12-07 Xcyte Therapies, Inc. Therapeutic uses of depsipeptides and congeners thereof
US20050070467A1 (en) * 2003-09-25 2005-03-31 Fujisawa Pharmaceutical Co., Ltd. Antitumor agent
US20050107290A1 (en) * 2003-06-27 2005-05-19 Fujisawa Pharmaceutical Co. Ltd. Therapeutic agent for soft tissue sarcoma
US20050187148A1 (en) * 2004-02-25 2005-08-25 Yoshinori Naoe Antitumor agent
US20050187149A1 (en) * 2004-02-25 2005-08-25 Yoshinori Naoe Antitumor agent
US20050191713A1 (en) * 2001-08-21 2005-09-01 Fujisawa Pharmaceutical Co.. Ltd. Medicinal use of histone deacetylase inhibitor and method of evaluating antitumor effect thereof
US20050261174A1 (en) * 2004-05-20 2005-11-24 Paul Lewer Insecticidal activity of a cyclic peptide
US20060106049A1 (en) * 2004-11-17 2006-05-18 The University Of Chicago Histone deacetylase inhibitors and methods of use
US20060135413A1 (en) * 2002-04-05 2006-06-22 Yoshinori Naoe Depsipeptide for therapy of kidney cancer
US20070129290A1 (en) * 2005-11-18 2007-06-07 Or Yat S Metabolite derivatives of the HDAC inhibitor FK228
US20080124403A1 (en) * 2006-06-08 2008-05-29 Gloucester Pharmaceuticals Deacetylase inhibitor therapy
US20080233562A1 (en) * 2003-02-19 2008-09-25 Astellas Pharma Inc. Method of Estimating Antitumor Effect of Histone Deacetylase Inhibitor
US20090131390A1 (en) * 2005-06-02 2009-05-21 Arasu Ganesan FK 228 derivates as HDAC inhibitors
US20090186382A1 (en) * 2006-12-29 2009-07-23 Verdine Gregory L Preparation of Romidepsin
US20090305956A1 (en) * 2006-04-24 2009-12-10 Gloucester Pharmaceuticals, Inc. Treatment of Ras-Expressing Tumors
US20100093610A1 (en) * 2006-12-29 2010-04-15 Vrolijk Nicholas H Romidepsin-based treatments for cancer
US20100261878A1 (en) * 2007-02-08 2010-10-14 Uwm Research Foundation, Inc. Sequences for fk228 biosynthesis and methods of synthesizing fk228 and fk228 analogs
US20110060021A1 (en) * 2009-08-19 2011-03-10 Yiqiang Cheng Histone deacetylase inhibitors and uses thereof
WO2012009336A1 (fr) 2010-07-12 2012-01-19 Gloucester Pharmaceuticals, Inc. Formes solides de la romidepsine et leurs utilisations
WO2012037008A2 (fr) 2010-09-13 2012-03-22 Gloucester Pharmaceuticals, Inc. Traitement thérapeutique de la leucémie à réarrangement de mll
WO2013043967A1 (fr) 2011-09-23 2013-03-28 Celgene Corporation Romidepsine et 5-azacitidine pour l'utilisation dans le traitement d'un lymphome
WO2013049093A1 (fr) 2011-09-26 2013-04-04 Celgene Corporation Polythérapie pour des cancers chimiorésistants
WO2013085902A1 (fr) 2011-12-05 2013-06-13 The University Of Texas M.D. Procédés de polythérapie pour le traitement d'un cancer du sein inflammatoire
WO2013106696A1 (fr) 2012-01-12 2013-07-18 Celgene Corporation Formulations de la romidepsine et utilisations de celle-ci
US8558008B2 (en) 2013-02-28 2013-10-15 Dermira, Inc. Crystalline glycopyrrolate tosylate
WO2014039744A1 (fr) 2012-09-07 2014-03-13 Celgene Corporation Biomarqueurs de résistance aux inhibiteurs de hdac
CN103877010A (zh) * 2012-12-21 2014-06-25 正大天晴药业集团股份有限公司 一种罗米地辛溶液的制备方法
CN104072589A (zh) * 2013-03-29 2014-10-01 浙江海正药业股份有限公司 抗肿瘤三硫化合物及其制备方法与应用
WO2015100399A1 (fr) 2013-12-27 2015-07-02 Celgene Corporation Formulations de la romidepsine et utilisations de celles-ci
US9101579B2 (en) 2012-11-14 2015-08-11 Celgene Corporation Inhibition of drug resistant cancer cells
WO2016210292A1 (fr) 2015-06-25 2016-12-29 Children's Medical Center Corporation Procédés et compositions se rapportant à l'expansion, l'enrichissement et la conservation de cellules souches hématopoïétiques
US20170073374A1 (en) * 2014-03-04 2017-03-16 Concord Biotech Limited A process for isolation pf romidepsin from fermentation broth and preparation of crystals of romidepsin
WO2017068596A1 (fr) * 2015-10-20 2017-04-27 Msn Laboratories Private Limited Procédé amélioré pour la préparation de (1s, 4s, 7z, 10s, 16e, 21r)- 7-éthylidène-4,21-bis(1-méthyléthyl)-2-oxa-12,13-dithia-5, 8, 20, 23- tétraazabicyclo[8.7.6]tricos-16-ène-3, 6, 9, 19, 22-pentone
WO2017161001A1 (fr) 2016-03-15 2017-09-21 Children's Medical Center Corporation Procédés et compositions concernant l'expansion de cellules souches hématopoïétiques
US10543192B2 (en) 2013-02-28 2020-01-28 Dermira, Inc. Glycopyrrolate salts
WO2020123242A1 (fr) 2018-12-14 2020-06-18 Pioneer Hi-Bred International, Inc. Produits biologiques et leur utilisation chez des végétaux
US11291651B2 (en) 2013-02-28 2022-04-05 Journey Medical Corporation Glycopyrrolate salts

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PT1142905E (pt) 1999-01-13 2006-10-31 Astellas Pharma Inc Novo composto de depsipeptido
WO2005058298A2 (fr) * 2003-12-10 2005-06-30 Wisconsin Alumni Research Foundation Analogues de fk228 et methodes de production et d'utilisation desdits analogues
AR080234A1 (es) * 2010-02-25 2012-03-21 Marrone Bio Innovations Inc Cepa bacteriana aislada del genero burkholderia y metabolitos pesticidas del mismo
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WO2013047509A1 (fr) 2011-09-30 2013-04-04 国立大学法人東北大学 Nouvel inhibiteur de phosphatidylinositol-3-kinase et composition pharmaceutique
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CN104447950A (zh) * 2013-09-18 2015-03-25 上海医药工业研究院 一种罗米地辛的分离纯化方法
CN104450837B (zh) * 2013-09-18 2019-01-01 上海医药工业研究院 一种用于生产罗米地辛的方法及发酵培养基
CN104894195B (zh) * 2014-03-07 2018-11-13 上海医药工业研究院 一种提高fk228产量的发酵培养基
CN104262456B (zh) * 2014-09-11 2018-01-09 浙江海正药业股份有限公司 一种罗米地辛的新晶型及其制备方法和用途
EP3902908A4 (fr) * 2018-12-24 2024-01-03 Pro Farm Group, Inc. Méthode d'augmentation de production de romidepsine à partir d'un bouillon de fermentation

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Cited By (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5130414A (en) * 1989-11-30 1992-07-14 Arizona Board Of Regents, A Body Corporate Of Arizona State University Isolation and structural elucidation of the cyclic peptide hymenistatin 1
US5428175A (en) * 1993-02-22 1995-06-27 Snow Brand Milk Products Co., Ltd. Physiologically active compound
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DK366889D0 (da) 1989-07-25
GB8817743D0 (en) 1988-09-01
NO893021D0 (no) 1989-07-25
CN1040054A (zh) 1990-02-28
CA1335083C (fr) 1995-04-04
JPH0764872B2 (ja) 1995-07-12
ES2058411T3 (es) 1994-11-01
EP0352646B1 (fr) 1993-09-15
IL90949A0 (en) 1990-02-09
JPH0285296A (ja) 1990-03-26
EP0352646A2 (fr) 1990-01-31
FI893359A0 (fi) 1989-07-11
HU211514A9 (en) 1995-11-28
EP0352646A3 (en) 1990-10-31
ATE94561T1 (de) 1993-10-15
AU3829089A (en) 1990-02-01
DE68909139T2 (de) 1994-02-10
FI893359A (fi) 1990-01-27
NO893021L (no) 1990-01-29
DE68909139D1 (de) 1993-10-21
DK366889A (da) 1990-01-27
ZA895121B (en) 1990-08-29

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